Chiral peptides

Abstract

The present disclosure provides certain chiral peptide agents, and uses relating thereto.

1 - 75 . (canceled) 
     
     
         76 . A tetrameric peptide agent of formula I:
   X 1 —X 2 —X 3 —X 4   I
   wherein:   X 1  is the N-terminal amino acid and X 4  is the C-terminal amino acid;   X 1  comprises an N-terminal moiety selected from the group consisting of —N(R) 2  and —N(R)—C(O)—R;   X 4  comprises a C-terminal moiety selected from the group consisting of —C(O)OR and —C(O)N(R) 2 ;   each R is independently hydrogen or optionally substituted C 1-6  aliphatic;   X 2  and X 4  are cationic amino acids; and   each of X 1 , X 2 , and X 3  is a D-amino acid, and X 4  is an L-amino acid.   
     
     
         77 . The tetrameric peptide agent of  claim 76 , wherein X 1  comprises an N-terminal moiety —N(R) 2 . 
     
     
         78 . The tetrameric peptide agent of  claim 76 , wherein X 4  comprises a C-terminal moiety —C(O)N(R) 2 . 
     
     
         79 . The tetrameric peptide agent of  claim 76 , wherein R is H. 
     
     
         80 . The tetrameric peptide agent of  claim 76 , wherein each cationic amino acid is independently selected from the group consisting of D-Arg, L-Arg, D-Lys, L-Lys, D-Orn, and L-Orn. 
     
     
         81 . The tetrameric peptide agent of  claim 76 , wherein X 1  and X 3  are hydrophobic, hydrophilic, or polar amino acids. 
     
     
         82 . The tetrameric peptide agent of  claim 81 , wherein each hydrophobic amino acid is independently selected from the group consisting of D-Leu and D-Phe. 
     
     
         83 . The tetrameric peptide agent of  claim 81 , wherein each hydrophilic or polar amino acid is independently selected from the group consisting of D-Tyr and D-Dmt. 
     
     
         84 . The tetrameric peptide of  claim 76 , wherein the peptide is selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                 
                   Peptide 
                     
                 
                   Number 
                   Peptide Sequence 
                 
                     
                 
                   I-16 
                   (D-Phe)(D-Orn)(D-Tyr)(L-Arg)-NH 2   
                 
                   I-17 
                   (D-Phe)(D-Orn)(D-Tyr)(L-Orn)-NH 2   
                 
                   I-18 
                   (D-Phe)(D-Lys)(D-Dmt)(L-Arg)-NH 2   
                 
                   I-19 
                   (D-Phe)(D-Orn)(D-Dmt)(L-Arg)-NH 2   
                 
                   I-20 
                   (D-Phe)(D-Orn)(D-Dmt)(L-Orn)-NH 2   
                 
                   I-34 
                   (D-Phe)(D-Lys)(D-Leu)(L-Arg)-NH 2   
                 
                   I-35 
                   (D-Phe)(D-Orn)(D-Leu)(L-Arg)-NH 2   
                 
                   I-36 
                   (D-Phe)(D-Orn)(D-Leu)(L-Orn)-NH 2   
                 
                   I-37 
                   (D-Leu)(D-Orn)(D-Leu)(L-Orn)-NH 2  and 
                 
                   I-38 
                   (D-Phe)(D-Orn)(D-Phe)(L-Orn)-NH 2 . 
                 
                     
                 
             
                
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         85 . The tetrameric peptide agent of  claim 76 , wherein the peptide agent is in a salt form. 
     
     
         86 . The tetrameric peptide agent of  claim 81 , wherein the salt form is a pharmaceutically acceptable salt form. 
     
     
         87 . A pharmaceutical composition comprising the tetrameric peptide agent of  claim 76  and a pharmaceutically acceptable excipient. 
     
     
         88 . The pharmaceutical composition of  claim 87 , wherein the pharmaceutical composition is formulated for oral delivery. 
     
     
         89 . A method of inhibiting mitochondrial respiration in a patient or in a biological sample, the method comprising a step of administering to said patient or contacting said biological sample with the a tetrameric peptide agent of formula I:
   X 1 —X 2 —X 3 —X 4   I
   wherein:   X 1  is the N-terminal amino acid and X 4  is the C-terminal amino acid;   X 1  comprises an N-terminal moiety selected from the group consisting of —N(R) 2  and —N(R)—C(O)—R;   X 4  comprises a C-terminal moiety selected from the group consisting of —C(O)OR and —C(O)N(R) 2 ;   each R is independently hydrogen or optionally substituted C 1-6  aliphatic;   X 2  and X 4  are cationic amino acids; and   each of X 1 , X 2 , and X 3  is a D-amino acid, and X 4  is an L-amino acid.   
     
     
         90 . The method of  claim 89 , wherein the tetrameric peptide agent is in a salt form. 
     
     
         91 . The method of  claim 90 , wherein the salt form is a pharmaceutically acceptable salt form. 
     
     
         92 . The method of  claim 89 , wherein the tetrameric peptide agent is administered to said patient. 
     
     
         93 . The method of  claim 92 , wherein the tetrameric peptide agent is administered in a pharmaceutical composition comprising a pharmaceutically acceptable excipient. 
     
     
         94 . The method of  claim 93 , wherein the tetrameric peptide agent is administered orally. 
     
     
         95 . The method of  claim 94 , wherein the patient has a disease, disorder, or condition is associated with mitochondrial dysfunction.